Ovarian steroids potently influence extra hypothalamic brain sties and can effect diverse functions as cognition. The cholinergic basal forebrain (CBF) and dopaminergic (DA) mesocortical systems are sensitive to levels of circulating estrogen in rodents. These cortically projecting systems are also integrally involved in higher order cognitive functions such that cognitive deficits occur when these systems are destroyed by experimental lesions or degenerative disease. Estrogen can influence brain function through genomic or non-genomic mechanisms. With regards to the CBF, estrogen receptors are located upon a sub-population of cholinergic neurons in rats suggesting a genomic mechanism of action. In contrast, such receptors are not found within the same population in monkey, suggesting that estrogen functions via non-genomic mechanisms in primates. For this, as well as other reasons, studies investigating the role of estrogen in cognitive processes may benefit by using non-human primates as an animal model. The present study employs four Specific Aims. In all experiments, circulating estrogens will be modulated via ovariectomy (OVX) followed by estrogen replacement (OVX + ERT) in both young and aged Rhesus monkeys. We will first examine the effects of OVX and OVX + ERT upon molecular, morphological, and neurochemical measurements of cholinergic enzymes, and a quantitative assessment of cholinergic gene expression and protein measurements of cholinergic enzymes, and a quantitative assessment of cholinergic gene expression and protein. The CBF is a system which is exquisitely sensitive to the trophic influences of trophic factors. Thus, the second Specific Aim will establish whether modulation of circulating estrogens via OVX and OVX + ERT will alter the gene expression and protein for neurotrophins (NGF and BDNF) and neurotrophin receptors (trkA and P75NTR). The third Specific Aim will establish whether modulation of circulating estrogens via OVX and OVX + ERT alters the number of DA mesocortical neurons, the protein and gene expression for tyrosine hydroxylase and dopamine transporter within these cells, as well as dopamine levels within the target regions within the prefrontal cortex. In Specific Aim 4, the most consistent and potent changes observed in Specific Aims 1-3 will be evaluated in OVX and OVX-ERT treated monkeys which have been behaviorally characterized. The relationship between the molecular, morphological, and neurochemical alterations mediated by estrogen and the cognitive status of the monkeys will be established.